Intracellular sclerostin promotes tumor progression and metastasis as a potential therapeutic target in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) urgently requires promising therapeutic targets. This study identifies sclerostin, an osteocyte-derived secretory protein traditionally linked to bone homeostasis, as an unexpected intracellular oncogenic driver in TNBC. Although genetic ablation of sclerostin markedly suppresses tumor progression and lung metastasis, neither its antibody nor recombinant protein exerts any effects, excluding the role of extracellular sclerostin in TNBC. Genetic and pharmacological approaches (sclerostin aptamer-based proteolysis-targeting chimera with potent intracellular sclerostin-degrading activity, Apc101) show the emerging role of intracellular sclerostin in promoting TNBC progression and metastasis. Notably, in both TNBC cell-derived and patient-derived xenograft models, Apc101 significantly suppresses tumor progression. Mechanistically, intracellular sclerostin interacts with caprin1 to stabilize CDK1 and Cyclin B1 mRNAs. Collectively, this study reveals an oncogenic function of intracellular sclerostin in TNBC and proposes that targeting it represents a promising therapeutic strategy.